Martin LA, Ashwood P, Braunschweig D, Cabanlit M, Van de Water J, Amaral DG. Stereotypies and hyperactivity in rhesus monkeys exposed to IgG from mothers of children with autism. Brain Behav Immun 22: 806-816

Department of Psychiatry and Behavioral Sciences, Center for Neuroscience, California National Primate Research Center and The MIND Institute, University of California-Davis, 2825 50th Street, Sacramento, CA 95817, USA.
Brain Behavior and Immunity (Impact Factor: 5.89). 09/2008; 22(6):806-16. DOI: 10.1016/j.bbi.2007.12.007
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Autism together with Asperger syndrome and pervasive developmental disorder not otherwise specified form a spectrum of conditions (autism spectrum disorders or ASD) that is characterized by disturbances in social behavior, impaired communication and the presence of stereotyped behaviors or circumscribed interests. Recent estimates indicate a prevalence of ASD of 1 per 150 (Kuehn, 2007). The cause(s) of most cases of ASD are unknown but there is an emerging consensus that ASD have multiple etiologies. One proposed cause of ASD is exposure of the fetal brain to maternal autoantibodies during pregnancy [Dalton, P., Deacon, R., Blamire, A., Pike, M., McKinlay, I., Stein, J., Styles, P., Vincent, A., 2003. Maternal neuronal antibodies associated with autism and a language disorder. Ann. Neurol. 53, 533-537]. To provide evidence for this hypothesis, four rhesus monkeys were exposed prenatally to human IgG collected from mothers of multiple children diagnosed with ASD. Four control rhesus monkeys were exposed to human IgG collected from mothers of multiple typically developing children. Five additional monkeys were untreated controls. Monkeys were observed in a variety of behavioral paradigms involving unique social situations. Behaviors were scored by trained observers and overall activity was monitored with actimeters. Rhesus monkeys gestationally exposed to IgG class antibodies from mothers of children with ASD consistently demonstrated increased whole-body stereotypies across multiple testing paradigms. These monkeys were also hyperactive compared to controls. Treatment with IgG purified from mothers of typically developing children did not induce stereotypical or hyperactive behaviors. These findings support the potential for an autoimmune etiology in a subgroup of patients with neurodevelopmental disorders. This research raises the prospect of prenatal evaluation for neurodevelopmental risk factors and the potential for preventative therapeutics.

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Available from: Judy Van de Water, Oct 04, 2015
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    • "Maternal antibodies from the human mother of a child with ASD were injected into a pregnant mouse and the offspring of the mouse demonstrated behavioral changes, despite the fact that the pregnant mouse did not exhibit any abnormalities [35] [36] [37]. Similar studies were performed on rhesus monkeys with similar results [38] [39]. Additionally, recent research of maternal immune activation models suggests lasting changes in macrophage function [40]. "
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    ABSTRACT: Recent studies of Autism Spectrum Disorders (ASD) highlight hyperactivity of the immune system, irregular neuronal growth and increased size and number of microglia. Though the small sample size in many of these studies limits extrapolation to all individuals with ASD, there is mounting evidence of both immune and nervous system related pathogenesis in at least a subset of patients with ASD. Given the disturbing rise in incidence rates for ASD, and the fact that no pharmacological therapy for ASD has been approved by the Food and Drug Administration (FDA), there is an urgent need for new therapeutic options. Research in the therapeutic effects of mesenchymal stem cells (MSC) for other immunological and neurological conditions has shown promising results in preclinical and even clinical studies. MSC have demonstrated the ability to suppress the immune system and to promote neurogenesis with a promising safety profile. The working hypothesis of this paper is that the potentially synergistic ability of MSC to modulate a hyperactive immune system and its ability to promote neurogenesis make it an attractive potential therapeutic option specifically for ASD. Theoretical mechanisms of action will be suggested, but further research is necessary to support these hypothetical pathways. The choice of tissue source, type of cell, and most appropriate ages for therapeutic intervention remain open questions for further consideration. Concern over poor regulatory control of stem cell studies or treatment, and the unique ethical challenges that each child with ASD presents, demands that future research be conducted with particular caution before widespread use of the proposed therapeutic intervention is implemented.
    Medical Hypotheses 12/2014; 84(3). DOI:10.1016/j.mehy.2014.12.016 · 1.07 Impact Factor
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    • "In order to examine whether these maternal antibodies play a direct role in the pathology of ASD, several animal models have been conducted. Data from both rodent [18] [19] and non-human primate [20] [21] experiments suggest that maternal antibodies reactive to fetal brain proteins do indeed play a role in the pathology of a subset of ASD. While informative, these prior animal studies have relied on passive transfer techniques to examine the effect of autism-specific antibodies on offspring behavior. "
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    ABSTRACT: Multiple studies have implicated a role of maternal autoantibodies reactive against fetal brain proteins specific to autism in the etiology of autism spectrum disorders (ASD). In the current study, we examined the impact of brain-reactive maternal autoantibodies of mothers of children with autism (MAU) on offspring behavior in mice compared to offspring exposed to non-reactive IgG of mothers of typically developing children (MTD). Embryonic offspring were exposed to a single intraventricular injection of MAU or MTD IgG on embryonic day 14. Offspring were allowed to mature to adulthood and were subsequently tested for sociability and stereotypic behaviors using a 3-chambered social approach task, marble burying task, and assessment of spontaneous grooming behaviors in response to a novel environment. Results indicate that MAU offspring display autistic-like stereotypic behavior in both marble burying and spontaneous grooming behaviors. Additionally, small alterations in social approach behavior were also observed in MAU offspring compared to MTD offspring. This report demonstrates for the first time the effects of a single, low dose intraventricular exposure of IgG derived from individual MAU samples on offspring behavior.
    Behavioural brain research 06/2014; 266:46-51. DOI:10.1016/j.bbr.2014.02.045 · 3.03 Impact Factor
    • "Although many neurodevelopmental disorders are thought to have a major genetic component, other components, such as environmental impact and associated gene–environment interactions have also been proposed (van Os et al., 2010). Interestingly, a role for maternal autoantibodies has been reported in a few neurodevelopmental phenotypes, e.g., autism, specific language difficulties, and dyslexia (Warren et al., 1990; Vincent et al., 2002, 2003; Dalton et al., 2003; Martin et al., 2008). "
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    ABSTRACT: Changes of voltage-gated ion channels and ligand-gated receptor channels caused by mutation or autoimmune attack are the cause of so-called channelopathies in the central and peripheral nervous system. We present the pathophysiology of channelopathies of the neuromuscular junction in terms of loss-of-function and gain-of-function principles. Autoantibodies generally have reduced access to the central nervous system, but in some cases this is enough to cause disease. A review is provided of recent findings implicating autoantibodies against ligand-activated receptor channels and potassium channels in psychiatric and neurological disorders, including schizophrenia and limbic encephalitis. The emergence of channelopathy-related neuropsychiatric disorders has implications for research and practice.
    Frontiers in Genetics 09/2013; 4:181. DOI:10.3389/fgene.2013.00181
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